Tandem oxidation processes: The direct conversion of activated alcohols into nitriles

Article abstract of DOI:10.1055/s-2002-32950

The direct conversion of primary alcohols into nitriles is reported (RCH₂OH into RCN) using manganese dioxide and ammonia in 2-propanol - THF, containing magnesium sulfate at room temperature. This transformation, which proceeds via an in situ

Full text of DOI:10.1055/s-2002-32950

LETTER
1291
Tandem Oxidation Processes: The Direct Conversion of Activated Alcohols
into Nitriles
T
G
andem
O
xidation
r
Process
a
es eme D. McAllister, Cecilia D. Wilfred, Richard J. K. Taylor*
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Fax +44(1904)434523; E-mail: rjkt1@york.ac.uk
Received 19 April 2002
the manganese dioxide. We hoped to illustrate that this
transformation could be carried out directly from primary
alcohols (Equation 2).
Abstract: The direct conversion of primary alcohols into nitriles is
reported (RCH OH into RCN) using manganese dioxide and am-
2
monia in 2-propanol–THF, containing magnesium sulfate at room
temperature. This transformation, which proceeds via an in situ ox-
idation-imination-aldimine oxidation sequence, has been applied to
a range of benzylic, heterocyclic, allylic and propargylic alcohols.
Initial studies were carried out using 4-bromobenzyl alco-
5
hol under Lai’s conditions (Equation 3). To our delight
the procedure gave the corresponding benzonitrile in 81%
Key words: oxidation, imines, nitriles, cyanides, one-pot
6,7
isolated yield.
N
NH3-IPA
MgSO4
C
As part of a programme to investigate tandem manganese
dioxide-mediated alcohol oxidation followed by in situ
trapping of the resulting aldehydes, we have studied the
OH
81%
MnO2
Br
Br
THF, r.t., 18 h
1
use of stabilised phosphoranes, non-stabilised phospho-
2
2
3
Equation 3
ranes, stabilised phosphonate anions and amines as
4
trapping agents. By including a polymer-supported re-
ducing agent in the amine trapping process, the sequence We therefore investigated the in situ oxidation-nitrile for-
was extended so that the intermediate imine was reduced mation reaction with a range of benzylic alcohols under
in situ: this oxidation-imination-reduction sequence thus these conditions (Table 1). They all underwent smooth
provides a one-pot route from alcohols to amines (Equa- transformation to give the corresponding nitriles in good
3
5
tion 1). Inspired by a recent publication by Lai et al., we yields. The reaction was compatible with electron with-
decided to investigate the related oxidation-imination-ox- drawing or donating substituents (entries i–iii), and effi-
idation sequence shown in Equation 2.
ciently
converted
1,4-benzenedimethanol
into
terephthalonitrile (entry iv). One naphthalene example
was studied and proceeded smoothly (entry v), as did the
conversion of indole-3-methanol into 3-cyanoindole (en-
try vi). In the last example it is noteworthy that N-protec-
tion was not required.
MnO2
[H]
ArCH NR1
1
ArCH NHR
ArCH OH
ArCHO
2
2
1
R NH2
PCSBH
PCSBH = polymer supported cyanoborohydride
We next looked at similar reactions with allylic and prop-
argylic alcohols (Table 2). Both E- and Z-non-2-en-1-ol
underwent efficient conversion into the corresponding un-
saturated nitriles (entries i and ii), although in the latter
example there was a small amount of alkene isomerisation
Equation 1
MnO2
[O]
RCH OH
RCHO
RCH NH
RC N
2
(
Z:E = 5:1). Propargyl alcohols were also studied (entries
NH3
iii and iv): both non-2-yn-1-ol and 3-phenylprop-2-yn-1-
ol gave the corresponding nitriles in good yields, the latter
reaction taking only 2 hours.
Equation 2
Lai’s group showed that aromatic aldehydes could be con-
verted into the corresponding nitriles by treatment with
ammonia in 2-propanol (IPA) and THF containing mag-
nesium sulfate and manganese dioxide at room tempera-
ture (r.t.) for 16–22 hours.5 This transformation
presumably involves conversion of the aldehyde into the
corresponding aldimine followed by in situ oxidation by
If the reaction with 3-phenylprop-2-yn-1-ol was left for
longer than 2 hours, increasing amounts of phenylpropar-
gylamide were observed, presumably by nitrile hydration
8
occurring in situ. A similar result was obtained with py-
ridine-2-methanol (Equation 4).8 A fair yield (30%) of
the nitrile was obtained under the standard (18 h) condi-
tions, but the main product was the corresponding carbox-
amide.
,9
Synlett 2002, No. 8, Print: 30 07 2002.
Art Id.1437-2096,E;2002,0,08,1291,1292,ftx,en;D08802ST.pdf.
Attempts to extend this methodology to unactivated alco-
hols such as decanol were unsuccessful.
1b
©
Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1
292
G. D. McAllister et al.
LETTER
Table 1 In Situ Oxidation-Imination-Oxidation Giving Nitriles:a
NH -IPA
3
Aromatic Examples
MgSO4
+
OH
MnO2
THF, r.t., 18 h
N
Entry Alcohol
Product
Product
isolated
N
N
C
CONH2
(
N
yield)
3
0%
60%
(
(
(
(
i)
N
81%
Equation 4
OH
C
Br
oxidant is heterogenous and can be removed by simple fil-
tration, evaporation of the solvent then giving the product.
Given the importance of nitriles for the synthesis of fine
chemicals, pharmaceuticals and agrochemicals, we feel
that this new methodology will be of general interest.
Br
ii)
iii)
iv)
N
81%
87%
78%
OH
C
10
O2N
O2N
N
OH
OH
C
Acknowledgement
We are grateful to the EPSRC for postdoctoral support (G. D. M.)
and to Universiti Teknologi, Petronas, Malaysia for a Scholarship
(C. D. W.).
OH
N
OH
C
HO
C
N
References
(
(
a
v)
OH
N
C
82%
77%
(
1) (a) Wei, X.; Taylor, R. J. K. Tetrahedron Lett. 1998, 39,
3815. (b) Blackburn, L.; Wei, X.; Taylor, R. J. K. Chem.
Commun. 1999, 1337. (c) Wei, X.; Taylor, R. J. K. J. Org.
Chem. 2000, 65, 616. (d) Runcie, K. A.; Taylor, R. J. K.
Chem. Commun. 2002, 974.
(2) Blackburn, L.; Pei, C.; Taylor, R. J. K. Synlett 2002, 215.
(3) Blackburn, L.; Taylor, R. J. K. Org. Lett. 2001, 3, 1637.
(4) For other tandem oxidation processes see the preceding and
following papers in this series.
vi)
OH
N
C
N
H
(5) (a) Lai, G.; Bhamare, N. K.; Anderson, W. K. Synlett 2001,
230. (b) See also: Gilman, N. W. J. Chem. Soc., Chem.
Commun. 1971, 733.
N
H
Using ammonia in IPA, MgSO , manganese dioxide (15 equiv) in
4
(
6) The products, which are all known, gave consistent
spectroscopic data (and mps if solids).
7
THF at r.t. for 18 h; 30 equiv of MnO was used in example (iv).
2
(
7) Representative experimental: A 2 M solution of ammonia in
2
-propanol (2.2 mL, 4.28 mmol; Aldrich) and anhydrous
Table 2 In Situ Oxidation-Imination-Oxidation Giving Nitriles: Al-
magnesium sulfate (1.93 g, 16.0 mmol) were added to a
stirred solution of 4-bromobenzyl alcohol (0.200 g, 1.07
mmol) in THF (4.3 mL). Activated manganese dioxide
lylic and Propargylic Examplesa
Entry Alcohol
Product
Product
isolated
(
Aldrich 21764-6; 1.40 g, 16.10 mmol) was added to the
(
solution. The resulting mixture was stirred at room
temperature for 18 hours and then diluted with dichloro-
yield)
®
methane (20 mL). The mixture was filtered through Celite ,
the Celite washed well with dichloromethane and the
(
(
(
i)
N
N
82% (24
h)
®
C6H13
C H
OH
OH
C
C
C6H13
C6H13
combined filtrates concentrated under reduced pressure. The
solid residue was purified by column chromatography (silica
gel, EtOAc–petroleum ether, 1:4) to give 4-bromobenzo-
nitrile (157 mg, 81%) as a white solid, mp 112.8 °C,
published mp (Aldrich) 112–114 °C.
ii)
iii)
iv)
82% (24
h) Z:E=5:1
6
13
OH
C H
C
N
87% (18
h)
6
13
C6H13
Ph
(8) Treatment of 2-cyanopyridine with ammonia in 2-propanol
and THF containing magnesium sulfate and manganese
dioxide at r.t. for 18 hours gave unreacted nitrile (30%) and
carboxamide (50%). The fact that the nitrile appears to be
formed first and is then converted into the carboxamide,
appears to rule out a mechanism involving oxidation of an
(
OH
Ph
C
N
82% (2 h)b
a
Using ammonia in IPA, MgSO , manganese dioxide (15 equiv.) in
4
THF at r.t. for the time indicated.
b
intermediate RCH(OH)NH species.
When the reaction was left for 3 h, some phenylpropargylamide was
2
observed by TLC. If the reaction was left for 24 h, phenylpropargyl-
amide was the only product (62%).
(9) Carboxamides were also observed with furan- and thio-
phene-methanols.
(
10) (a) For recent references see: Yang, S. H.; Chang, S. Org.
Lett. 2001, 3, 4209. (b) Srinivas, K. V. N.; Reddy, E. B.;
Das, B. Synlett 2002, 625. (c) Baxendale, I. R.; Ley, S. V.;
Sneddon, H. F. Synlett 2002, 775.
In conclusion, we have successfully developed a one-pot
procedure for the conversion of activated primary alco-
hols into nitriles which is extremely easy to perform as the
Synlett 2002, No. 8, 1291–1292 ISSN 0936-5214 © Thieme Stuttgart · New York